PROJECT SUMMARY/ABSTRACT Prostate cancer is a large public health burden, with about 170,000 men diagnosed annually in the US. The majority of men diagnosed with prostate cancer will not die from their cancer even if it is not treated, leading to the recommendation of active surveillance for the approximately 75,000 low risk prostate cancers diagnosed each year. Active surveillance protocols vary, but all involve monitoring, usually by PSA testing and prostate biopsy, with curative treatment recommended only if there are indications that more aggressive cancer may be present. Yet, emerging data from randomized studies suggest that with limited monitoring significantly more men have clinical progression or develop metastatic cancer when compared to those who undergo immediate curative treatment. There is an urgent need for markers that improve risk stratification for men who are candidates for active surveillance. Better risk stratification will improve patient selection for active surveillance, will identify appropriate and timely triggers for curative treatment, and will optimize and personalize surveillance regimens, e.g. how often to perform surveillance prostate biopsy. Many commercially available molecular biomarker assays have been developed for prostate cancer detection or for prognosis of higher risk cancers, and several of these are being marketed as assays that determine treatment versus surveillance for newly diagnosed prostate cancer, but no biomarkers have been tested or validated specifically in the active surveillance population. In this proposal, we will utilize existing commercially available assays that incorporate analytically validated molecular biomarkers and evaluate them for a novel use of predicting clinically meaningful endpoints in active surveillance. We will employ a prospective-retrospective design to interrogate well-annotated biospecimens from the large multi-center Canary Prostate Active Surveillance Study (PASS) cohort. The Canary PASS program is a multi-disciplinary group with clinical investigators (urology, medical oncology, pathology), statisticians, and clinical laboratory scientists. In collaboration with commercial partners, Canary PASS is optimally poised to validate assays so that they can be integrated into clinical practice in the near term. For the work in this proposal we will leverage collaborations with three industry partners (GenomeDx, MDxHealth, OPKO Diagnostics) to validate tissue, urine, and blood-based biomarkers for use in active surveillance. Successful implementation of assays for improved risk stratification and prognosis in active surveillance patients will reduce overtreatment and improve surveillance regimens without increasing cancer deaths.